Combination therapy comprising SIRP alpha fusion protein and anti-CD19 antibody for treatment of cancer

Abstract

Combination therapies comprising a SIRPaFc fusion protein and an anti-CD19 agent are provided. The combination therapy may optionally further comprise an E3 ubiquitin ligase modulator.

Description

[0001] References to Electronic Sequence Listings

[0002] The contents of the electronic Sequence Listing (P113970010WO00-SEQ-LJG.xml; size: 26,811 bytes; and creation date: May 25, 2023) are incorporated herein by reference in their entirety. Background Art

[0003] The antibody binds to cancer cell antigens and recruits and activates macrophages by binding to the Fc portion of the antibody through Fc receptors, thereby targeting and destroying cancer cells. The binding transmission between CD47 on cancer cells and SIRPα ("SIRPα") on macrophages allows many tumor cells to escape the "don't eat me" signal of macrophage destruction. Studies have shown that inhibiting the CD47 / SIRPα interaction (CD47 blockade) will allow macrophages to "see" and destroy target CD47+ cancer cells. The use of SIRPα to treat cancer through CD47 blockade is described in WO 2010 / 130053, which is incorporated herein by reference.

[0004] International Patent Application Publication No. WO 2014 / 094122, which is incorporated by reference in its entirety, describes a protein drug that inhibits the interaction between CD47 and SIRPα. The CD47 blocking drug is a form of human SIRPα that incorporates a specific region of its extracellular domain linked to a particularly useful form of an IgG-based Fc region. In this form, the SIRPαFc drug exhibits a significant effect on the viability of cancer cells that exhibit a CD47+ phenotype. This effect is particularly evident in acute myeloid leukemia (AML) cells and many other types of cancer.

[0005] CD19 is a 95-kDa transmembrane glycoprotein of the immunoglobulin superfamily, containing two extracellular immunoglobulin-like domains and a huge cytoplasmic tail. The protein is a pan-B lymphocyte surface receptor, and is ubiquitously expressed from the earliest stage of pre-B cell development until it is downregulated during terminal differentiation into plasma cells. The protein is specific to the B lymphocyte lineage, and except for some follicular dendritic cells, it is not expressed on hematopoietic stem cells and other immune cells. CD19 acts as a positive regulator of B cell receptor (BCR) signal transduction, and is crucial for B cell activation and proliferation and in the development of humoral immune response. It acts as a costimulatory molecule in combination with CD21 and CD81, and is crucial for the response of B cells to T cell-dependent antigens. The cytoplasmic tail of CD19 is physically related to the tyrosine kinase family that triggers downstream signal transduction pathways via the src family of protein tyrosine kinases. CD19 is an attractive target for cancers of lymphoid origin because it is highly expressed in nearly all chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), as well as in many other different types of leukemia, including acute lymphoblastic leukemia (ALL) and hairy cell leukemia (HCL).

[0006] Tafasitamab (formerly known as MOR208 and 5574) is a humanized monoclonal antibody targeting the antigen CD19 (a transmembrane protein involved in B cell receptor signaling). Tafacitumomab has been engineered in the IgG Fc region to enhance antibody-dependent cell-mediated cytotoxicity (ADCC), thereby improving the key mechanism of tumor cell killing and providing the potential for enhanced efficacy compared to conventional antibodies (i.e., non-enhanced antibodies). Tafacitumomab has been or is currently being studied in multiple clinical trials, such as in CLL, ALL, and NHL. Tafacitumomab received accelerated approval from the U.S. Food and Drug Administration (FDA) in July 2020 for use in combination with lenalidomide for the treatment of adult patients with R / R DLBCL. In August 2021, the European Commission authorized the marketing authorization of tafacitumomab in combination with lenalidomide, followed by tafacitumomab monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not suitable for autologous stem cell transplantation (ASCT). Despite the recent discovery and development of several anti-cancer agents, due to the poor prognosis of many types of cancer, including CD19-expressing tumors, there remains a need for improved methods or therapeutics for treating such cancers.

[0007] Therefore, there is a need for improved dosing regimens and therapeutic methods using SIRPαFc agents and CD19 targeting agents. Summary of the invention

[0008] Provided herein are therapies that combine SIRPαFc fusion proteins and CD19 targeting agents. Provided herein are dosing regimens and methods that include both SIRPαFc fusion proteins and anti-CD19 antibodies. These combination therapies may also include E3 ubiquitin ligase modulators.

[0009] In some embodiments, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a combination of a SIRPαFc fusion protein and an anti-CD19 antibody.

[0010] In some embodiments, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a combination therapy of a SIRPαFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator for at least a first cycle, a second cycle, a third cycle, and a fourth cycle, wherein each cycle is 28 days, wherein in the first cycle, the SIRPαFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 4, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21, wherein in the second cycle, the SIRPαFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 4, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21. on days 1, 8, 15 and 22, the anti-CD19 antibody is administered on days 1, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21, wherein in a third cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15 and 22, the anti-CD19 antibody is administered on days 1, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21, and wherein in a fourth cycle, the SIRPaFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase modulator is administered on days 1-21.

[0011] In some embodiments, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a combination therapy of a SIRPαFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator for at least a first cycle, a second cycle, a third cycle, and a fourth cycle, wherein each cycle is 28 days, wherein in the first cycle, the SIRPαFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg on days 1, 8, 15, and 22. The anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, wherein in the second cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, and the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15 and 22 , and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, wherein in the third cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, wherein in the fourth cycle , the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1 and 15, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, and wherein the SIRPaFc fusion protein is TTI-622, the anti-CD19 antibody is tafamidis, and the E3 ubiquitin ligase modulator is lenalidomide. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1Depicted is an exemplary regimen for combination therapy combining TTI-622 (SIRPaFc fusion protein), tafasitumab (anti-CD19 antibody), and lenalidomide (E3 ubiquitin ligase modulator). DETAILED DESCRIPTION

[0013] The present invention can be more easily understood by reference to the following detailed description of embodiments of the present invention and the examples included herein. It should be understood that the present invention is not limited to specific preparation methods, which can certainly be changed. It should also be understood that the terms used herein are only used to describe the purpose of specific embodiments and are not intended to be limiting.

[0014] Exemplary embodiments (E) of the invention provided herein include:

[0015] E1. A method of treating cancer in a patient comprising administering to the patient a combination of a SIRPαFc fusion protein and an anti-CD19 antibody.

[0016] E2. The method of E1, wherein the method further comprises administering an E3 ubiquitin ligase regulator.

[0017] E3. The method of any one of E1-E2, wherein the SIRPαFc fusion protein is administered Q1W or Q2W.

[0018] E4. The method of any one of E1-E3, wherein the anti-CD19 antibody is administered Q1W or Q2W.

[0019] E5. The method of any one of E1-E4, wherein the E3 ubiquitin ligase modulator is administered daily.

[0020] E6. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy of a SIRPαFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator for at least a first cycle, a second cycle, a third cycle, and a fourth cycle,

[0021] Each cycle is 28 days.

[0022] wherein in the first cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 4, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21,

[0023] wherein in the second cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21,

[0024] wherein in the third cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21, and

[0025] Wherein in the fourth cycle, the SIRPaFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase regulator is administered on days 1-21.

[0026] E7. The method of E6, wherein the method continues for at least the fifth cycle and up to the twelfth cycle, and in the fifth cycle to the twelfth cycle, the SIRPαFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase modulator is administered on days 1-21.

[0027] E8. The method of E7, wherein the method continues for at least a thirteenth cycle, wherein in the thirteenth cycle, the SIRPαFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase modulator is not administered.

[0028] E9. The method of any one of E1-E8, wherein the SIRPαFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg.

[0029] E10. The method of any one of E1-E9, wherein the anti-CD19 antibody is administered at a dose of 12 mg / kg.

[0030] E11. The method of any one of E1-E10, wherein the E3 ubiquitin ligase modulator is administered at a dose of 25 mg.

[0031] E12. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy of a SIRPαFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator for at least a first cycle, a second cycle, a third cycle, and a fourth cycle,

[0032] Each cycle is 28 days.

[0033] wherein in the first cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21,

[0034] wherein in the second cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21,

[0035] wherein in the third cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, and

[0036] Wherein in the fourth cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1 and 15, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21.

[0037] E13. The method of E12, wherein the method continues for at least the fifth cycle and up to the twelfth cycle, and in the fifth cycle to the twelfth cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1 and 15, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21.

[0038] E14. The method of E13, wherein the method continues for at least a thirteenth cycle, wherein in the thirteenth cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1 and 15, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15, and the E3 ubiquitin ligase modulator is not administered.

[0039] E15. The method of any one of E1-E14, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO: 1.

[0040] E16. The method of any one of E1-E15, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO:2.

[0041] E17. The method of any one of E1-E16, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:7.

[0042] E18. The method of any one of E1-E16, wherein the SIRPaFc fusion protein comprises the amino acid sequence of SEQ ID NO:8.

[0043] E19. The method of any one of E1-E15, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO: 1, or a variant thereof having one, two, three, four or five amino acid substitutions compared to the sequence of SEQ ID NO: 1.

[0044] E20. A method as described in any one of E1-E19, wherein the anti-CD19 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 11), a HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 12), and a HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 13), and the light chain variable region comprising a LCDR1 region comprising the sequence RSSKSLQNVNGNTY LY (SEQ ID NO: 14), a LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 15), and a LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 16).

[0045] E21. The method of any one of E1-E20, wherein the anti-CD19 antibody comprises a heavy chain variable region of EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPG KGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRS EDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 17) and a light chain variable region of DIVMTQSPATLSLSPGERATLSCRSSKSLQNVN GNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTL TISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 18).

[0046] E22. The method of any one of E1-E21, wherein the anti-CD19 antibody comprises an Fc domain comprising an amino acid substitution at position S239 and / or I332, wherein the numbering is according to the EU index as in Kabat.

[0047] E23. The method of E22, wherein the anti-CD19 antibody comprises an Fc domain comprising an S239D amino acid substitution and an I332E amino acid substitution, wherein the numbering is according to the EU index in Kabat.

[0048] E24. The method of any one of E1-E23, wherein the anti-CD19 antibody comprises EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKAL PAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ The heavy chain region of ID NO:19) and DIVMTQSPATLSLSPGERATLSC RSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:20) light chain region.

[0049] E25. The method of any one of E1-E24, wherein the E3 ubiquitin ligase modulator comprises lenalidomide, pomalidomide or thalidomide.

[0050] E26. The method of any one of E1-E25, wherein the E3 ubiquitin ligase modulator is lenalidomide.

[0051] E27. The method of any one of E1-E26, wherein the E3 ubiquitin ligase modulator is administered orally.

[0052] E28. The method of any one of E1-E27, wherein the SIRPαFc fusion protein and the anti-CD19 antibody are administered intravenously or subcutaneously.

[0053] E29. The method of any one of E1-E28, wherein the cancer is a CD19-positive cancer.

[0054] E30. The method of any one of E1-E29, wherein the cancer is a CD47-positive cancer.

[0055] E31. The method of any one of E1-E30, wherein the cancer is a hematological malignancy or a solid tumor cancer.

[0056] E32. The method of any one of E1-E31, wherein the cancer is lymphoma or leukemia.

[0057] E33. The method of any one of E1-E32, wherein the cancer is chronic lymphocytic leukemia, acute lymphocytic leukemia, or non-Hodgkin's lymphoma.

[0058] E34. A method as described in any of E1-E33, wherein the cancer is a non-Hodgkin's lymphoma selected from the group consisting of follicular lymphoma (FL), small lymphocytic lymphoma, mucosa-associated lymphoid tissue lymphoma, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma.

[0059] E35. A SIRPαFc fusion protein or an anti-CD19 antibody for use in treating a patient according to any one of the methods of E1-E34.

[0060] E36. Use of a SIRPαFc fusion protein or an anti-CD19 antibody in the preparation of a medicament for treating a patient according to any one of the methods of E1-E34.

[0061] E37. A kit comprising a SIRPαFc fusion protein or an anti-CD19 antibody and instructions for use of the method according to any one of claims 1-34, and optionally further comprising one or more additional therapeutic agents according to the method according to any one of E1-E34.

[0062] Without being bound by theory, in the combination methods provided herein involving a SIRPαFc fusion protein (e.g., TTI-622), an anti-CD19 antibody (e.g., tafacitumab), and an E3 ubiquitin ligase modulator (e.g., lenalidomide), it is believed that one or more of the following anti-cancer effects may occur in view of the combination treatment: 1) increased antibody-dependent cellular phagocytosis (ADCP): tafacitumab and lenalidomide increase the "eat" signal, while TTI-622 blocks the "don't eat me" signal on tumor cells; 2) increased antibody-dependent cellular cytotoxicity (ADCC): lenalidomide lowers the threshold for NK cell activation, thereby promoting tafacitumab-mediated ADCC; 3) directed killing: lenalidomide has direct tumor killing activity. These activities may occur in various cancer types, such as DLBCL.

[0063] In some embodiments, the present disclosure relates to the use of a SIRPαFc fusion protein in combination with an anti-CD 19 antibody for treating cancer in a patient.

[0064] In some embodiments, the disclosure relates to a composition comprising a SIRPαFc fusion protein for use in treating a patient's cancer, wherein the patient is also treated with an anti-CD 19 antibody. In some aspects, the disclosure relates to a composition comprising a SIRPαFc fusion protein for use in treating a patient's condition that is cancer, wherein the SIRPαFc fusion protein is combined with an anti-CD 19 antibody. In some embodiments, the SIRPαFc fusion protein can be administered simultaneously or sequentially with the anti-CD 19 antibody.

[0065] In some embodiments, the disclosure relates to methods of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a combination of a SIRPαFc fusion protein and an anti-CD19 antibody.

[0066] In some embodiments, the present disclosure relates to methods of treating cancer by administering to a patient a combination of a SIRPαFc fusion protein, or a pharmaceutically acceptable salt thereof, and an anti-CD19 antibody.

[0067] In another aspect, the present disclosure relates to the use of a SIRPαFc fusion protein in combination with an anti-CD19 antibody for treating cancer.

[0068] In some embodiments, the method of treating cancer as described herein may include a combination of a SIRPαFc fusion protein and an anti-CD19 antibody and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents may be chemotherapeutic agents. In some embodiments, the one or more additional therapeutic agents may include, but are not limited to, lenalidomide, fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate anthracycline-based chemotherapeutic agents, prednisone, methylprednisolone, glucocorticoids, ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof.

[0069] In some embodiments, a method of treating cancer as described herein may include a combination of a SIRPαFc fusion protein, an anti-CD19 antibody, and lenalidomide.

[0070] In some embodiments, a method of treating cancer as described herein may include a combination of a SIRPαFc fusion protein and an anti-CD19 antibody, wherein the anti-CD19 antibody is tafacitumab, and wherein tafacitumab is administered at a dose of 12 mg / kg body weight.

[0071] In some embodiments, the methods of treating cancer as described herein may include a combination of a SIRPαFc fusion protein and an anti-CD19 antibody, wherein the SIRPαFc fusion protein is TTI-622, and wherein TTI-622 is administered at 4 mg / kg, 10 mg / kg, or 18 mg / kg, or 300 mg, 600 mg, 750 mg, 1200 mg / kg on days 1, 8, 15, and 22 of the first, second, and third 28-day cycles and on days 1 and 15 of subsequent 28-day cycles. The invention relates to a method of administering a fixed dose of 12 mg / kg body weight of 1, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg body weight, wherein the anti-CD19 antibody is tafacitumomab, and wherein tafacitumomab is administered at a dose of 12 mg / kg body weight on Days 1, 4, 8, 15 and 22 of the first 28-day cycle and on Days 1, 8, 15 and 22 of the second and third 28-day cycles and on Days 1 and 15 of one or more subsequent cycles.

[0072] In some embodiments, the method of treating cancer as described herein may include a combination of a SIRPαFc fusion protein, an anti-CD 19 antibody, and lenalidomide, wherein the SIRPαFc fusion protein is TTI-622, and wherein TTI-622 is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg body weight, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg, wherein the anti-CD 19 antibody is tafasitumab, and wherein tafasitumab is administered at a dose of 12 mg / kg body weight, and wherein lenalidomide is administered at a dose of 25 mg.

[0073] In some embodiments, the method of treating cancer as described herein may include a combination of a SIRPαFc fusion protein, an anti-CD 19 antibody, and lenalidomide, wherein the SIRPαFc fusion protein is TTI-622, and wherein TTI-622 is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg body weight, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg, wherein the anti-CD 19 antibody is tafasitumab, and wherein tafasitumab is administered at a dose of 12 mg / kg body weight, and wherein lenalidomide is administered at a dose of 25 mg on days 1 to 21 of a 28-day cycle.

[0074] In some embodiments, the methods of treating cancer as described herein may include a combination of a SIRPαFc fusion protein, an anti-CD19 antibody, and lenalidomide, wherein the SIRPαFc fusion protein is TTI-622, and wherein TTI-622 is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg body weight or 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 2000 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7500 mg, 8000 mg, 9000 mg, 10000 mg, 15000 mg, 20000 mg, 20000 mg, 30000 mg, 40000 mg, 50000 mg, 60000 mg, 75000 mg, 80000 mg, 90000 mg, 100000 mg, 200000 mg, 300000 mg, 400000 mg, 500000 mg, The invention relates to a method of treating a 28-day cycle in which the anti-CD19 antibody is administered at a fixed dose of 12 mg / kg body weight on days 1, 4, 8, 15 and 22 of a first 28-day cycle and on days 1, 8, 15 and 22 of a second and third 28-day cycle and on days 1 and 15 of one or more subsequent cycles, and wherein lenalidomide is administered at a dose of 25 mg on days 1 to 21 of a 28-day cycle.

[0075] In some embodiments, the cancer is a CD19-positive cancer.

[0076] In some embodiments, the cancer is a blood cancer. Non-limiting examples of blood cancers include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated CML and CML blast phase (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma (HL); non-Hodgkin's lymphoma (NHL), including B-cell lymphoma, T-cell lymphoma, follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and leukemia. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma or non-Hodgkin's lymphoma, including follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma.

[0077] In some embodiments, the cancer is chronic lymphocytic leukemia. In some embodiments, the cancer is CD19 positive chronic lymphocytic leukemia.

[0078] In some embodiments, cancer is non-Hodgkin's lymphoma, including follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma. In some embodiments, cancer is B-cell lymphoma. In some embodiments, cancer is CD19 positive non-Hodgkin's lymphoma. In some embodiments, cancer is CD19 positive aggressive non-Hodgkin's lymphoma. In some embodiments, cancer is CD19 positive indolent non-Hodgkin's lymphoma. In some embodiments, cancer is relapsed or refractory non-Hodgkin's lymphoma. In some embodiments, cancer is relapsed or refractory CD19 positive aggressive non-Hodgkin's lymphoma. In some embodiments, cancer is relapsed or refractory CD19 positive indolent non-Hodgkin's lymphoma.

[0079] In some embodiments, the cancer is recurrent. In some embodiments, a recurrent cancer is a cancer that appears again after a period of time in which the cancer was not detected.

[0080] In some embodiments, the cancer is refractory. In some embodiments, refractory cancer does not respond to cancer treatment; it is also called resistant cancer. In some embodiments, the cancer is resistant to rituximab. In some embodiments, the cancer does not respond to treatment with rituximab. In some embodiments, the cancer is a rituximab-resistant recurrent cancer. In some embodiments, the patient becomes refractory to a regimen containing rituximab. In some embodiments, the tumor is unresectable. In some embodiments, an unresectable tumor cannot be removed by surgery. In some embodiments, the cancer has not been treated previously. In some embodiments, the cancer is locally advanced. In some embodiments, "locally advanced" refers to a cancer that is somewhat extensive but still confined to one area. In some cases, "locally advanced" may refer to a small tumor that has not yet spread but has invaded nearby organs or tissues that makes it difficult to remove with surgery alone. In some embodiments, the cancer is metastatic. In some embodiments, metastatic cancer is a cancer that spreads from the part of the body (primary site) where it started to one or more other parts of the body.

[0081] In some embodiments, the patient suffers from relapsed or refractory CD19-positive non-Hodgkin's lymphoma.In some embodiments, the patient suffers from both CD19-positive non-Hodgkin's lymphoma and relapsed or refractory non-Hodgkin's lymphoma.

[0082] In some embodiments, the patient has relapsed or refractory CD19-positive aggressive non-Hodgkin's lymphoma. In some embodiments, the patient has relapsed or refractory CD19-positive aggressive non-Hodgkin's lymphoma and has undergone at least one prior treatment regimen.

[0083] In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin's lymphoma. In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin's lymphoma and has undergone at least two prior treatment regimens. In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin's lymphoma and is refractory to any anti-CD20 monoclonal antibody or any anti-CD19 monoclonal antibody. In some embodiments, the patient has relapsed or refractory CD19-positive indolent non-Hodgkin's lymphoma and has undergone at least two prior treatment regimens and is refractory to any anti-CD20 monoclonal antibody.

[0084] In some embodiments, the present disclosure relates to a medicament for treating cancer in a patient in need of such treatment. The medicament comprises a SIRPαFc fusion protein and an anti-CD19 antibody and is in a single dosage form or in separate dosage forms.

[0085] In some embodiments, a medicament as described herein may include a combination of a SIRPαFc fusion protein, an anti-CD19 antibody, and optionally one or more additional therapeutic agents.

[0086] In some embodiments, the disclosure relates to the use of a SIRPαFc fusion protein in the preparation of a medicament for treating cancer, wherein the SIRPαFc fusion protein is administered with an anti-CD19 antibody, and wherein the medicament is a single dosage form or separate dosage forms. In some embodiments, the SIRPαFc fusion protein is administered with an anti-CD19 antibody and one or more additional therapeutic agents.

[0087] In some embodiments, the disclosure relates to the use of a SIRPαFc fusion protein in the preparation of a medicament for treating cancer in a patient, wherein the patient is also treated with an anti-CD 19 antibody and optionally one or more additional therapeutic agents. In some embodiments, the SIRPαFc fusion protein can be administered simultaneously or sequentially with the anti-CD 19 antibody.

[0088] In another aspect, the present disclosure relates to the use of a SIRPαFc fusion protein in combination with an anti-CD19 antibody in the preparation of a medicament for treating cancer. In some embodiments, the present disclosure relates to the use of a SIRPαFc fusion protein in combination with an anti-CD19 antibody and optionally one or more additional therapeutic agents in the preparation of a medicament for treating cancer.

[0089] In another aspect, the disclosure relates to the use of a SIRPαFc fusion protein in the preparation of a medicament for treating cancer, wherein the SIRPαFc fusion protein is administered together with an anti-CD19 antibody and optionally one or more additional therapeutic agents.

[0090] In some embodiments, the one or more additional therapeutic agents may be chemotherapeutic agents. In some embodiments, the one or more additional therapeutic agents may include, but are not limited to, fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate anthracycline-based chemotherapeutic agents, prednisone, methylprednisolone, glucocorticoids, ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof.

[0091] In one aspect, the disclosure relates to an anti-CD 19 antibody for use in treating cancer, wherein the anti-CD 19 antibody is administered in combination with a SIRPαFc fusion protein to a subject in need of such treatment.

[0092] In one aspect, the disclosure relates to an anti-CD 19 antibody for use in treating cancer, wherein the anti-CD 19 antibody is administered in combination with a SIRPαFc fusion protein.

[0093] In some embodiments, the SIRPαFc fusion protein may be administered in combination with an anti-CD19 antibody and optionally one or more additional therapeutic agents in a single dosage form or as separate dosage forms. In some embodiments, when administered as separate dosage forms, the anti-CD19 antibody may be administered before, simultaneously with, or after the administration of the SIRPαFc fusion protein. In some embodiments, when administered as separate dosage forms, one or more doses of the SIRPαFc fusion protein may be administered before the anti-CD19 antibody. In some embodiments, the anti-CD19 antibody is administered before the SIRPαFc fusion protein is administered. As used herein, the "combination" administration of the SIRPαFc fusion protein, the anti-CD19 antibody, and optionally one or more additional therapeutic agents refers not only to the simultaneous or sequential administration of these agents, but also to the administration of these agents during a single treatment cycle, as understood by those skilled in the art. When the SIRPαFc fusion protein is administered in combination with the anti-CD19 antibody and optionally one or more additional therapeutic agents, a therapeutically effective amount of the combination is administered.

[0094] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0095] All references cited herein, including patent applications, patent publications, UniProtKB accession numbers, are hereby incorporated by reference as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety.

[0096] The techniques and procedures described or referenced herein are generally well understood and commonly employed by those skilled in the art using routine methods, such as the widely used methods described in the following references: Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (FM Ausubel et al., eds., (2003)); METHODS IN ENZYMOLOGY series (Academic Press, Inc.); PCR 2: A PRACTICAL APPROACH (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)); Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JECellis editor, 1998) Academic Press; Animal Cell Culture (RI Freshney) editor, 1987); Introduction to Cell and Tissue Culture (JPMather and PERoberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (edited by A.Doyle, JBGriffiths and DG Newell, 1993-8) J.Wiley and Sons; Handbook of Experimental Immunology (edited by DMWeir and CC Blackwell); Gene Transfer Vectors for Mammalian Cells (JMMiller and MPEdited by Calos, 1987); PCR: The Polymerase Chain Reaction, (edited by Mullis et al., 1994); Current Protocols in Immunology (edited by JEColigan et al., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CAJaneway) and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (edited by D. Catty., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (edited by P. Shepherd and C. Dean, Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and their updated versions.

[0097] definition

[0098] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by one of ordinary skill in the art.

[0099] As used herein, the singular forms "a", "an", and "the" include plural references unless otherwise indicated. For example, "an" antibody includes one or more antibodies.

[0100] When aspects or embodiments of the invention are described in terms of Markush groups or other alternative groupings, the invention encompasses not only the entire group listed as a whole, but also each member of the individual groups and all possible subgroups of the main group, as well as the main group lacking one or more of the group members. The invention also contemplates the explicit exclusion of one or more of any group members in the claimed invention.

[0101] The term "such as" or any examples following "for example" are not meant to be exhaustive or limiting.

[0102] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of a SIRPαFc fusion protein or an anti-CD19 antibody) means that the parameter may be up to 10% lower or higher than the stated value of the parameter. For example, a dosage of about 5 mg means 5% ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0103] The terms "treating," "treat," or "treatment" refer to any type of treatment, such as to alleviate, lessen, or slow the progression of a patient's disease, disorder, or condition, or any tissue damage associated with the disease. In some embodiments, the disease, disorder, or condition is cancer.

[0104] The term "therapeutically effective amount" refers to the amount of an active ingredient that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following: (1) preventing disease; e.g., preventing a disease, disorder or condition in an individual who may be susceptible to the disease, disorder or condition but does not yet experience or display the pathology or symptoms of the disease; (2) inhibiting disease; e.g., inhibiting a disease, disorder or condition in an individual who is experiencing or displaying the pathology or symptoms of the disease, disorder or condition (i.e., arresting or slowing the further development of the pathology or symptoms); and (3) ameliorating disease; e.g., ameliorating a disease, disorder or condition in an individual who is experiencing or displaying the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology or symptoms).

[0105] SIRPaFc fusion protein

[0106] The present invention provides a combination therapy including a SIRPα-Fc ("SIRPαFc") ​​fusion protein. The dosing regimens and methods provided herein use CD47 binding and blocking forms of SIRPα as CD47 blocking drugs or blocking agents. An agent or drug having CD47 blocking activity is an agent that interferes with and inhibits the signaling generated when CD47 interacts with SIRPα presented by macrophages. The CD47 binding form of human SIRPα is a preferred CD47 blocking drug for the regimens and methods provided herein. These drugs are based on the extracellular region of human SIRPα. They contain at least one region of the extracellular region sufficient to confer effective CD47 binding affinity and specificity. The so-called "soluble" forms of SIRPα lacking membrane anchoring components are described in the literature and include those mentioned in WO 2010 / 070047 (Novartis), WO 2013 / 109752 (Stanford), and WO 2014 / 094122 (Trillium), each of which is incorporated by reference in its entirety.

[0107] In a preferred embodiment, the soluble form of SIRPα is an Fc fusion. More specifically, the drug suitably comprises a human SIRPα protein in a direct or indirect fusion form with an antibody constant region or Fc (fragment crystallizable). Unless otherwise indicated, as used herein, the term "human SIRPα" refers to the wild-type, endogenous, mature form of human SIRPα. In humans, the SIRPα protein is found in two major forms. One form, the variant 1 or V1 form, has an amino acid sequence as shown in NCBI RefSeq NP_542970.1 (residues 27-504 constitute the mature form). The other form, the variant 2 or V2 form, differs by 13 amino acids and has an amino acid sequence as shown in GenBank as CAA71403.1 (residues 30-504 constitute the mature form). These two forms of SIRPα constitute approximately 80% of the forms of SIRPα present in humans, and both forms are encompassed by the term "human SIRPα" herein. The term "human SIRPα" also includes its minor form which is endogenous to humans and has the same property of triggering signal transduction through CD47 when bound to CD47. The present invention most particularly relates to a pharmaceutical combination comprising the variant 2 form of human SIRPα, or V2.

[0108] In the dosing regimens and methods provided herein, useful SIRPαFc fusion proteins comprise one of the three so-called immunoglobulin (Ig) domains located within the extracellular region of human SIRPα. More specifically, the SIRPαFc proteins of the present invention incorporate residues 32-137 of human SIRPα (106-mer), which constitute and define the V2 form of the IgV domain according to current nomenclature. The SIRPα sequence shown below is referred to herein as SEQ ID NO: 1.

[0109] EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGP ARELIYNQKEGHFPRVTTVSESTKRENMDFSISNITPADAGTYYC VKFRKGSPDTEFKSGA[SEQ ID NO:1]

[0110] In some embodiments, the SIRPα Fc fusion protein incorporates the IgV domain defined by SEQ ID NO: 1 and additional flanking residues that are contiguous within the SIRPα sequence. The IgV domain of this form, represented by residues 31-148 of the V2 form of human SIRPα, is a 118-mer and has SEQ ID NO: 2 as shown below:

[0111] EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAG PARELIYNQKEGHFPRVTTVSESTKRENMDFSISNITPADAGTYY CVKFRKGSPDTEFKSGAGTELSVRAKPS[SEQ ID NO:2]

[0112] The SIRPα fusion proteins of the present invention may also incorporate an Fc region with effector function. Fc refers to "fragment crystallizable" and represents an antibody constant region consisting primarily of components within the heavy chain constant region and the hinge region. Suitable Fc components include those with effector function. An Fc component "with effector function" is an Fc component that has at least some effector function, such as at least some contribution to antibody-dependent cellular toxicity or some ability to fix complement. Moreover, the Fc will at least bind to an Fc receptor. These properties can be revealed using assays established for this purpose. Functional assays include standard chromium release assays that detect target cell lysis. By this definition, the Fc region of wild-type IgG1 or IgG4 has effector function, while the Fc region of human IgG4 that has been mutated to eliminate effector function (such as by incorporating an altered series including Pro233, Val234, Ala235 and a deletion of Gly236 (EU)) is considered to have no effector function. In some embodiments, the Fc is based on a human antibody of the IgG1 isotype. The Fc region of these antibodies is readily identified by those skilled in the art. In an embodiment, the Fc region includes the lower hinge-CH2-CH3 domain.

[0113] In a specific embodiment, the Fc region is based on the amino acid sequence of human IgG1 shown in UniProtKB / Swiss-Prot as P01857, residues 104-330, and has the amino acid sequence shown below and referred to herein as SEQ ID NO:3:

[0114] DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[SEQ ID NO:3]

[0115] Therefore, in some embodiments, the Fc region has a wild type or consensus sequence of an IgG1 constant region. In an alternative embodiment, the Fc region incorporated in the fusion protein is derived from any IgG1 antibody with a typical effector activity constant region. The sequence of such Fc regions can correspond to the Fc region of any of the following IgG1 sequences (all cited from GenBank), for example: BAG65283 (residues 242-473), BAC04226.1 (residues 247-478), BAC05014.1 (residues 240-471), CAC20454.1 (residues 99-320), BAC05016.1 (residues 238-469), BAC85350.1 (residues 243-474), BAC85529.1 (residues 244-475) and BAC85429.1 (residues 238-469).

[0116] In other embodiments, the Fc region has the sequence of a wild-type human IgG4 constant region. In alternative embodiments, the Fc region incorporated into the fusion protein is derived from any IgG4 antibody having a constant region that has effector activity, but the potency of the naturally occurring region is significantly lower than that of the IgG1 Fc region. The sequence of such an Fc region can correspond to, for example, the Fc region of any of the following IgG4 sequences: P01861 (residues 99-327) from UniProtKB / Swiss-Prot and CAC20457.1 (residues 99-327) from GenBank.

[0117] In some embodiments, the Fc region is based on the amino acid sequence of human IgG4 shown in UniProtKB / Swiss-Prot as P01861, residues 99-327, and has the amino acid sequence shown below and referred to herein as SEQ ID NO:4:

[0118] ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[SEQ ID NO:4]

[0119] In some embodiments, the Fc region incorporates one or more alterations, generally no more than about 10, such as up to 1, 2, 3, 4, 5, or 6 such alterations, including amino acid substitutions that affect certain Fc properties. In a specific and preferred embodiment, the Fc region incorporates an alteration at position 228 (EU numbering) in which the serine at that position is replaced by a proline (S 228 P) substitutions to stabilize the disulfide bonds within the Fc dimer. Other changes within the Fc region may include substitutions that alter glycosylation, such as substitutions of Asn with glycine or alanine. 297 ; Changes that increase half-life, such as T 252 L.T 253 S and T 256 F, as taught in US62777375 and many other documents. Particularly useful are those changes that enhance Fc properties while maintaining conformational silencing (e.g., maintaining Fc receptor binding). In another embodiment, the Fc region is modified to increase its biological half-life. A variety of methods are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Patent No. 6,277,375.

[0120] In a specific embodiment, and where the Fc component is an IgG4 Fc, the Fc incorporates at least S 228 P mutation, and having the amino acid sequence shown below and referred to herein as SEQ ID NO:5:

[0121] ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[SEQ ID NO:5]

[0122] Therefore, the CD47 blocking drug used in the schemes and methods provided herein is preferably a SIRPα fusion protein, which can be used to inhibit the binding of human SIRPα to human CD47, thereby inhibiting or reducing CD47-mediated signal transduction via SIRPα binding, the fusion protein comprising a human SIRPα component and an Fc component fused thereto, wherein the SIRPα component comprises or consists of a single IgV domain of human SIRPα V2, and the Fc component is a constant region of human IgG with effector function.

[0123] In one embodiment, the fusion protein comprises a SIRPα component consisting of at least residues 32-137 of the V2 form of wild-type human SIRPα (i.e., SEQ ID NO: 1). In a preferred embodiment, the SIRPα component consists of residues 31-148 of the V2 form of human SIRPα (i.e., SEQ ID NO: 2). In another embodiment, the Fc component is the Fc component of human IgG1 designated P01857, and in a specific embodiment, has the amino acid sequence incorporated into its lower hinge-CH2-CH3 region, i.e., SEQ ID NO: 3.

[0124] In some embodiments, the SIRPαFc fusion protein is provided and used in a secreted dimer fusion form, wherein the fusion protein incorporates a SIRPα component having SEQ ID NO: 1 and preferably SEQ ID NO: 2 and fused thereto an Fc region having effector function and having SEQ ID NO: 3. When the SIRPα component is SEQ ID NO: 1, the fusion protein comprises SEQ ID NO: 6, as shown below:

[0125] EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0126] [SEQ ID NO:6]

[0127] When the SIRPa component is SEQ ID NO:2, the fusion protein comprises SEQ ID NO:7, as shown below:

[0128] EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELS VRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0129] [SEQ ID NO:7]

[0130] The SIRPαFc fusion protein of SEQ ID NO: 7 is also known as TTI-621.

[0131] In an alternative embodiment, the Fc component of the fusion protein is based on IgG4, and preferably based on incorporation of S 228 In the case where the fusion protein incorporates the preferred SIRPα IgV domain of SEQ ID NO: 2, the resulting IgG4-based SIRPα-Fc protein has SEQ ID NO: 8, as shown below:

[0132] EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQF NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[SEQ ID NO:8]

[0133] The SIRPαFc fusion protein of SEQ ID NO: 8 is also known as TTI-622.

[0134] In one embodiment of the dosing regimens or methods provided herein, the SIRPαFc fusion protein comprises as the SIRPα component of the fusion protein a sequence comprising SEQ ID NO: 2. In one embodiment, the SIRPαFc fusion protein comprises a polypeptide of SEQ ID NO: 7 or SEQ ID NO: 8.

[0135] As described in the literature, the SIRPα sequence incorporated into the SIRPαFc fusion protein can be varied. This can eliminate glycosylation sites in the protein, such as at position 89 and other positions. Other useful substitutions within SIRPα include one or more of the following substitutions: L4V / I, V6I / L, A21V, V27I / L, 131T / S / F, E47V / L, K53R, E54Q, H56P / R, S66T / G, K68R, V92I, F94V / L, V63I and / or F103V.

[0136] In a SIRPαFc fusion protein, the SIRPα component and the Fc component are fused directly or indirectly to provide a single-chain polypeptide, which may optionally ultimately be produced as a dimer, wherein the single-chain polypeptides are coupled via interchain disulfide bonds formed within the Fc region. The nature of the fusion region is not critical. The fusion may be performed directly between the two components, with the SIRPα component constituting the N-terminus of the fusion and the Fc component constituting the C-terminus. Alternatively, the fusion may be indirect, via a linker consisting of one or more amino acids, ideally genetically encoded amino acids, such as two, three, four, five, six, seven, eight, nine or ten amino acids, or any number of amino acids between 5 and 100 amino acids, such as 5 to 50, 5 to 30 or 5 to 20 amino acids. The linker may comprise a peptide encoded by DNA constituting a restriction site, such as BamHI, ClaI, EcoRI, HindIII, PstI, SalI and XhoI sites, among others.

[0137] The linker amino acids typically and ideally have some flexibility to allow the Fc and SIRPα components to adopt their active conformations. Residues that allow this flexibility are typically Gly, Asn, and Ser, so that almost any combination of these residues (particularly Gly and Ser) within the linker is likely to provide the desired connection effect. In one example, such a linker is based on the so-called G4S sequence (Gly-Gly-Gly-Gly-Ser [SEQ ID NO: 9]), which can be repeated as (G4S)n (SEQ ID NO: 21), where n is 1, 2, 3 or greater, or based on (Gly)n, (Ser)n, (Ser-Gly)n, or (Gly-Ser)n, etc. In another embodiment, the linker is GTELSVRAKPS [SEQ ID NO: 10]. This sequence constitutes a SIRPα sequence flanked by an IgV domain at the C-terminus (it should be understood that when coupled to the above-mentioned IgV minimal sequence, this flanking sequence can be considered a different form of a linker or an IgV domain). It is only necessary that the fusion region or linker allow the components to adopt their active conformation, and this may be achieved by any form of linker useful in the art.

[0138] The term "CD47 + "(or CD47+)" is used to refer to the phenotype of cells to which the polypeptide of the present invention targets. CD47 + Cells can be identified by flow cytometry using CD47 antibodies as affinity ligands. Appropriately labeled CD47 antibodies are commercially available for this purpose (e.g., clone B6H12 antibody products are available from Santa Cruz Biotechnology). Cells examined for CD47 phenotype may include standard tumor biopsy samples, particularly those taken from cells suspected of carrying endogenous CD47. + A blood sample of a subject with cancer cells. CD47 disease cells of particular interest as targets for treatment with the fusion proteins of the invention are those that "overexpress" CD47. These CD47 + The cell is typically a disease cell and presents CD47 on its surface at a density that exceeds the normal CD47 density of a given type of cell. CD47 overexpression will vary in different cell types, but refers herein to any CD47 level determined, for example, by flow cytometry as exemplified herein, or by immunostaining, or by gene expression analysis, etc., that is higher than the level measurable on a corresponding cell having a normal CD47 phenotype for that cell type.

[0139] The SIRPαFc fusion proteins provided herein can be administered at various doses ranging from about 0.0001 to 100 mg / kg.

[0140] In some embodiments, TTI-621 (SEQ ID NO:7) is administered in a range of 0.01 to 30 mg / kg of subject body weight. For example, the TTI-621 dose can be 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9.0 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg or 10.0 mg / kg.TTI-621 dosages may also include, for example, 0.2-2 mg / kg, 0.7-2 mg / kg, 1-5 mg / kg, 2-5 mg / kg, or 2-10 mg / kg. These doses of TTI-621 may be administered to a subject, for example, once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), twice a month, once a month, once every two months, or once every three months.

[0141] In some embodiments, TTI-622 (SEQ ID NO: 8) is administered in a range of 0.1 to 50 mg / kg of the subject's body weight. For example, the TTI-622 dose can be 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 31mg / kg, 32mg / kg, 33mg / kg, 34mg / kg, 35mg / kg, 36mg / kg, 37mg / kg, 38 mg / kg, 39mg / kg, 40mg / kg, 41mg / kg, 42mg / kg, 43mg / kg, 44mg / kg, 45mg / kg, 46mg / kg, 47mg / kg, 48mg / kg, 49mg / kg or 50mg / kg. TTI-622 dosages may also include, for example, 2-40 mg / kg, 4-40 mg / kg, 5-50 mg / kg, 8-50 mg / kg, 8-40 mg / kg, 8-30 mg / kg, 8-28 mg / kg, 10-50 mg / kg, 10-40 mg / kg, 10-30 mg / kg, 10-25 or 10-20 mg / kg. These doses of TTI-622 may be administered to a subject, for example, once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), twice a month, once a month, once every two months, or once every three months.

[0142] In some embodiments, a SIRPα Fc fusion protein provided herein [e.g., TTI-622 (SEQ ID NO: 8)] is administered at a "non-variable" (also referred to as a "fixed") dose - that is, the dose is an amount per patient, and the dose does not depend on the patient's weight. In some embodiments, a SIRPα Fc fusion protein such as TTI-622 is administered at 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg g, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 190 0mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 25 In some embodiments, the dosage is administered to the patient weekly (QW), every 2 weeks (Q2W), every 3 weeks (Q3W), or every 4 weeks (Q4W).

[0143] In some embodiments, the SIRPα Fc fusion protein is present in a) 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450 0, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150 or 2200 mg and b) 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150 or 1200 mg. 50, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2 550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, ​​3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550 or 3600 mg, wherein the lower limit level is a value less than the upper limit level.

[0144] The SIRPαFc proteins provided herein show negligible binding to red blood cells. Thus, there is no need to consider RBC "sinking" when administering with the SIRPαFc fusion proteins provided herein. Relative to other CD47 blocking drugs that are bound by RBC, it is estimated that the SIRPαFc fusions of the present invention can be effective at a dose less than half of the dose required for RBC-bound drugs (such as CD47 antibodies). In addition, the SIRPαFc fusion proteins provided herein are dedicated antagonists of SIRPα-mediated signals and, when bound thereto, they show negligible CD47 agonism. Thus, when formulating a medically useful unit dosage regimen, there is no need to consider any irritation caused by the drug.

[0145] Anti-CD19 agents

[0146] The term "CD19" refers to a protein called CD19, with the following synonyms: B4, B lymphocyte antigen CD19, B lymphocyte surface antigen B4, CVID3, differentiation antigen CD19, MGC12802, and T cell surface antigen Leu-12. The term also encompasses naturally occurring CD19 variants, such as splice variants, allelic variants, and isoforms.

[0147] "MOR208" and "XmAb 5574" and "tafacitumomab" are used as synonyms for anti-CD19 antibodies according to Table 1. Table 1 provides the amino acid sequence of MOR208 / tafacitumomab. The MOR208 antibody is described in U.S. Patent Application Serial No. 12 / 377,251, which is incorporated by reference in its entirety.

[0148] The term "anti-CD19 antibody" or "antibody that binds to CD19" refers to an antibody that is capable of binding to CD19 with sufficient affinity such that the antibody can be used as a diagnostic and / or therapeutic agent targeting CD19.

[0149] WO2007076950 (US2007154473) discusses the use of anti-CD19 antibodies in non-specific B-cell lymphomas, both of which are incorporated by reference in their entirety. S cheuermann et al., CD19 Antigen in Leukemia and Lymphoma Diagnosis and Immunotherapy, Leukemia and Lymphoma, Vol. 18, 385-397 (1995) describes the use of CD19 antibodies in CLL, NHL and ALL, which is incorporated by reference in its entirety.

[0150] WO2005012493 (US7109304), WO2010053716 (US12 / 266,999) (Immunomedics), WO2007002223 (US US8097703) (Medarex), WO 2008022152 (12 / 377,251) and WO2008150494 (Xencor), WO2008031056 (US11 / 852,106) (Medimmune), WO 2007076950 (US11 / 648,505) (Merck Patent GmbH), WO 2009 / 052431 (US12 / 253,895) (Seattle Genetics) and WO2010095031 (12 / 710,442) (Glenmark Pharmaceutica Other antibodies specific for CD19 are described in WO2012010562 and WO2012010561 (International Drug Development ), WO2011147834 (Roche Glycart) and WO2012156455 (Sanofi), all of which are incorporated by reference in their entirety.

[0151] In some embodiments, the anti-CD19 antibody used with the methods and compositions provided herein is tafacitumab (MOR208). Tafacitumab has the sequence shown in Table 1 below.

[0152] Table 1: Tafacitinib sequences

[0153]

[0154]

[0155] E3 ubiquitin ligase regulators

[0156] In some embodiments, the combination therapies provided herein include E3 ubiquitin ligase modulators. These modulators may also be referred to as immunomodulatory drugs (IMiDs). These modulators target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (referred to as CRL4 CRBN ) and promote CRL4 CRBN Ubiquitination of transcription factors IKZF1 and IKZF3. CRL4 CRBN Modulators of CRL4 include, for example, thalidomide, lenalidomide, and pomalidomide, which modulate CRL4 activity by binding to the CRBN subunit.

[0157] The dosage regimen and method provided herein can be used to treat a variety of cancer cells. These particularly include CD47 positive and / or CD19 positive cancer cells, including liquid (blood) and solid tumors. Solid tumors can be treated with the dosage regimen and method provided herein to reduce their size, quantity or growth rate and control the growth of cancer stem cells. Such solid tumors include CD47 positive and / or CD19 positive tumors in bladder, brain, breast, lung, colon, ovary, prostate, liver and other tissues. In one embodiment, the dosage regimen and method provided herein can be used to inhibit the growth or proliferation of blood cancers. As used herein, "blood cancer" refers to cancer of the blood, and includes leukemia, lymphoma and myeloma, etc. "Leukemia" refers to cancer of the blood, and the human body produces too many white blood cells, and these white blood cells cannot effectively resist infection, thereby crowding out other components in the blood, such as platelets and red blood cells. It is understood that cases of leukemia are classified as acute or chronic. Some forms of leukemia can be, for example, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative disorders / tumors (MPDS) and myelodysplastic syndromes." Lymphoma" can refer to Hodgkin's lymphoma, indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma and follicular lymphoma (small cells and large cells), etc. Myeloma can refer to multiple myeloma (MM), giant cell myeloma, heavy chain myeloma and light chain or Bence-Jones myeloma. In specific embodiments, the dosage regimen and methods provided herein can be used to treat T cell lymphoma (TCL), which is a group of very heterogeneous lymphoid malignancies divided into skin TCL and peripheral TCL, and itself is divided into nodal or extranodal types. CTCL arises from skin-homing T cells and consists of mycosis fungoides, Sézary syndrome, primary cutaneous T-cell lymphoproliferative disorder, and anaplastic large cell lymphoma. With the exception of ALK and ALCL, the common features of TCL are aggressive course and poor response to treatment.

[0158] In some other embodiments, the blood cancer treated with the dosing regimen and method is a CD47-positive or CD19-positive leukemia, preferably selected from acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and myelodysplastic syndrome, preferably human acute myeloid leukemia.

[0159] In other embodiments, the blood cancer treated with the dosing regimens or methods provided herein is a CD47-positive or CD19-positive lymphoma or myeloma selected from Hodgkin's lymphoma, indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, follicular lymphoma (small cell and large cell), multiple myeloma (MM), giant cell myeloma, heavy chain myeloma and light chain or Bence-Jones myeloma, and leiomyosarcoma.

[0160] The SIRPαFc fusion proteins or anti-CD19 antibodies provided herein can be administered to a subject by any route established for protein delivery, particularly intravenous, intradermal, and subcutaneous injection or infusion, or by oral or nasal administration.

[0161] Pharmaceutical compositions of SIRPαFc fusion proteins or anti-CD19 antibodies may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections. These injectable formulations may be prepared by known methods. For example, injectable formulations may be prepared, for example, by dissolving, suspending or emulsifying the above-mentioned fusion protein or antibody or a salt thereof in a sterile aqueous medium or an oily medium conventionally used for injection. Exemplary pharmaceutical compositions comprising antibodies specific for CD19 that can be used in the context of the present disclosure are disclosed, for example, in WO2008 / 022152 or WO2018 / 002031, which are incorporated by reference in their entirety.

[0162] The contents of U.S. Provisional Patent Application No. 63 / 351,117 filed on June 10, 2022 and U.S. Provisional Patent Application No. 63 / 494,500 filed on April 6, 2023 are incorporated herein by reference for all purposes.

[0163] The following examples, which are provided for specific aspects of practicing the invention, are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0164] The above description and the following examples describe in detail certain specific embodiments of the present disclosure and describe the best mode contemplated by the inventor. However, it should be understood that no matter how the details of the above content appear in the text, the present disclosure can be practiced in many ways, and the present disclosure should be interpreted according to the appended claims and any equivalents thereof.

[0165] Although the disclosed teachings have been described with reference to various applications, methods, kits and compositions, it should be understood that various changes and modifications may be made without departing from the teachings herein and the disclosures claimed below. The following examples are provided to better illustrate the disclosed teachings and are not intended to limit the scope of the teachings set forth herein. Although the present teachings have been described according to these exemplary embodiments, it will be readily appreciated by those skilled in the art that multiple variations and modifications may be made to these exemplary embodiments without excessive experimentation. All of these changes and modifications are within the scope of the current teachings.

[0166] Example

[0167] In order to better understand the present invention, the following examples are given. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0168] Example 1: TTI-622 versus tadalafil and lenalidomide in patients with diffuse large B-cell lymphoma Clinical Research

[0169] The purpose of this study was to evaluate the safety and preliminary efficacy of TTI-622 in combination with tadalafil and lenalidomide in patients with relapsed / refractory (R / R) diffuse large B-cell lymphoma (DLBCL) who were not eligible for stem cell transplantation.

[0170] This is a multicenter, international, 2-component (Phase 1b followed by Phase 2) study of TTI-622 in combination with tadalafil and lenalidomide in participants with RR DLBCL who have completed at least 1 line of systemic therapy (at least 1 line of anti-CD20-containing therapy) and are ineligible for autologous stem cell transplantation (ASCT) or are inoperable due to age ( > 70 years of age) or comorbidities that make them unable or unwilling to undergo ASCT and therefore unsuitable for intensive chemotherapy. In Part 2 of the study, participants may not have received more than 2 lines of prior therapy (induction, transplant, and consolidation will be considered first-line therapy). Prior treatment with CAR-T is allowed. In Part 2, no more than 5 patients who have received prior CAR-T will be allowed in the study.

[0171] Part 1 will be conducted in approximately 20 participants. The Phase 1b component, which will precede the dose optimization portion of the study (Part 2), aims to evaluate the safety and tolerability, PK, and PD of TTI-622 in combination with standard doses of tafamidis and lenalidomide.

[0172] Based on the Summary of Product Characteristics (SmPC) of tafacitinib and lenalidomide, an mTPI-2-guided step-up / step-down approach will be used in Phase 1b to determine the safe dose of TTI-622 when administered in combination with tafacitinib and lenalidomide. The TTI-622 dose levels to be studied are as follows:

[0173] Cohort 1 (DL1): 4 mg / kg or 300 mg fixed-dose TTI-622 QW C1-3, then C4+Q2W

[0174] Cohort 2 (DL2): 10 mg / kg or 750 mg fixed-dose TTI-622 QW C1-3, then C4+Q2W

[0175] Cohort 3 (DL3): 18 mg / kg or 1350 mg fixed-dose TTI-622 QW C1-3, then C4+Q2W

[0176] Treatment will be given in 28-day cycles. Lenalidomide will be administered until cycle 12, while TTI-622 and tafamidis will be administered until disease progression or unacceptable toxicity.

[0177] For Cycle 1, TTI-622 will be administered by IV infusion at doses of 4 mg / kg, 10 mg / kg, 18 mg / kg or a fixed dose of 300 mg, 750 mg, or 1350 mg on Days 1, 8, 15, and 22. Tafacitumomab will be administered by IV infusion at 12 mg / kg on Days 1, 4, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0178] For Cycle 2, TTI-622 will be administered by IV infusion at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg or a fixed dose of 300 mg, 750 mg, or 1350 mg on Days 1, 8, 15, and 22. Tafacitumomab will be administered by IV infusion at 12 mg / kg on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0179] For Cycle 3, TTI-622 will be administered by IV infusion at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg or a fixed dose of 300 mg, 750 mg, or 1350 mg on Days 1, 8, 15, and 22. Tafacitumomab will be administered by IV infusion at 12 mg / kg on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0180] For cycles 4-12, TTI-622 will be administered by IV infusion at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg or a fixed dose of 300 mg, 750 mg, or 1350 mg on days 1 and 15. Tafacitumomab will be administered by IV infusion at 12 mg / kg on days 1 and 15. Lenalidomide will be administered orally at 25 mg on days 1-21.

[0181] For cycles 13 and beyond, TTI-622 will be administered by IV infusion at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg or a fixed dose of 300 mg, 750 mg, or 1350 mg on days 1 and 15. Tafacitumomab will be administered by IV infusion at 12 mg / kg on days 1 and 15.

[0182] The dosing regimen is summarized in Table 2 below:

[0183] Table 2:

[0184]

[0185]

[0186] Figure 1A schematic diagram of the study is provided.

[0187] The sponsor may further increase the dose based on emerging PK, PD, efficacy and safety data. A safety review team composed of sponsor personnel, including at least one medically qualified member, together with the investigators and participants enrolled in the specific cohort, will review all safety data after each participant has been followed for at least 28 days from the first dose of the combination treatment. If a patient has received all applicable doses during the DLT observation period (see above) or has an adverse event (AE) that meets the DLT criteria during this time, it will be considered evaluable for DLT. If a patient has a non-DLT event and the dose needs to be maintained in accordance with the dose adjustment guidelines, more patients may be recruited. If DL3 is not tolerated, an additional cohort (DL4) may be studied in which 18 mg / kg TTI-622 (or another dose level lower than DL3 but higher than DL2) will be administered Q2W starting from C1.

[0188] At least 3 DLT-evaluable participants will be treated at each dose level of the combination therapy. Prior to entering Phase 2, at least 9 DLT-evaluable participants will be treated at the estimated MTD of TTI-622 or the highest tested dose level.

[0189] For Phase 2, the same or similar dosing regimen as used in Phase 1 described above may be used. Optionally, for Phase 2, the TTI-622 dose may be modified compared to the Phase 1 regimen such that TTI-622 is administered at a fixed dose of 300 mg, 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg instead of a body weight (mg / kg) dose. Optionally, when administered at a fixed dose, TTI-622 may be administered at the same frequency as the body weight-based dose provided in Phase 1.

[0190] Participants must meet the following key inclusion criteria to be eligible for this study:

[0191] Age and gender : An appropriately consenting male or female who is at least 18 years of age (or the minimum age of consent according to local regulations) willing and able to comply with all study visits and assessments.

[0192] Disease characteristics: Histologically confirmed relapsed and / or refractory CD19+ diffuse large B-cell lymphoma (not otherwise specified) with measurable progression; T-cell / histiocyte-rich large B-cell lymphoma, Epstein-Barr virus-positive DLBCL, grade 3b follicular lymphoma, or combined lymphoma with DLBCL components, followed by DLBCL relapse, histological transformation from an earlier diagnosed low-grade lymphoma to DLBCL (early diagnosed follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia). Progression after transformation to DLBCL must be observed before enrollment.

[0193] Patients who have received at least 1 prior line of systemic therapy and are deemed by the investigator to be unfit or unwilling to undergo high-dose chemotherapy or subsequent autologous stem cell transplantation. At least 1 line of prior therapy must have included anti-CD20-containing therapy. In Part 2, no more than 2 lines of prior systemic therapy were allowed.

[0194] Participants with any of the following characteristics / conditions will be excluded:

[0195] Medical conditions :

[0196] 1. Primary refractory DLBCL (response less than PR, or progression during or within 6 months after completion of first-line therapy).

[0197] 2. Double or triple DLBCL and CNS lymphoma. (Double / triple: Simultaneous detection of MYC and BCL2 and / or BCL6 translocation by fluorescence in situ hybridization. No MYC, BCL2, BCL6 testing is required before study entry.)

[0198] 3. History of any malignancy other than DLBCL, except for the following: adequately treated basal cell carcinoma or squamous cell carcinoma of the skin or Bowen's disease; previous transformation of follicular lymphoma to DLBCL; or any malignancy ≥3 years before randomization, regardless of stage, with no evidence of subsequent recurrence or progression after untreated treatment, or in situ, stage 0-1 cancer <3 years before randomization, with a low probability of recurrence or progression according to the investigator's judgment.

[0199] 4. Patients who have received cancer treatment before, received radiation therapy within 2 weeks, or underwent major surgery within 2 weeks, or had toxicity > grade 1 (except alopecia) not resolved by NCICTCAE v5.0.

[0200] 5. Patients who have received allogeneic stem cell transplantation before; patients who have received autologous stem cell transplantation within 12 weeks before enrollment, have active GVHD (except grade 1 skin involvement) or GVHD requiring treatment.

[0201] 6. Severe cardiovascular disease, such as symptomatic congestive heart failure (New York Heart Association class III or IV), symptomatic coronary artery disease, myocardial infarction, uncontrolled / unstable arrhythmias after treatment, unstable angina in the past 6 months, or prolonged QTcF interval >470 milliseconds at screening. LVEF <40% as determined by MUGA scan or ECHO. History of deep vein thrombosis or pulmonary embolism, threatening thromboembolism, or known thrombotic tendency. Participants must be willing to receive preventive treatment for thromboembolic events.

[0202] 7. Active hepatitis B or hepatitis C or known HIV or COVID-19 infection (symptomatic or asymptomatic) or any infection requiring systemic therapy:

[0203] Previous / concomitant treatment :

[0204] 1. Patients have received previous treatment with anti-CD47 or anti-CD19 (except CAR-T) or immunomodulators such as thalidomide or lenalidomide.

[0205] 2. Except for the administration of inactivated vaccines, the administration of live vaccines is prohibited within 4 weeks before randomization and during the trial.

[0206] 3. Use of corticosteroids, except for the following: intranasal, inhaled, eye drops, topical steroids, or local steroid injections (e.g., intra-articular injections); physiologic doses <10 mg / day of prednisone or equivalent doses of systemic corticosteroids.

[0207] The primary endpoint in Phase 1b is DLT during the DLT observation period. Analysis of DLTs is based on the DLT evaluable set. The incidence of DLTs and AEs constituting DLTs during the DLT observation period will be summarized and listed by dose level for participants enrolled in Phase 1b.

[0208] The primary endpoint of phase 2 is OR according to the Lugano Response Classification Criteria 2014 as assessed by the investigator. Participants who do not have a post-baseline tumor assessment due to early disease progression, who receive anticancer therapy other than study intervention before achieving a CR or PR, or who die from any cause, have documented PD, or discontinue tumor assessment before achieving a CR or PR will be counted as nonresponders in the assessment of ORR. ORR will be calculated with a two-sided 95% CI using the Clopper-Pearson method.

[0209] Exemplary dosing regimens for Phase 2 and beyond include the following:

[0210] Regimen: 600mg TTI-622:

[0211] Treatment will be given in 28-day cycles. Lenalidomide will be administered until cycle 12, while TTI-622 and tafamidis will be administered until disease progression or unacceptable toxicity.

[0212] For Cycle 1, TTI-622 will be administered at a fixed dose of 600 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 4, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0213] For Cycle 2, TTI-622 will be administered at a fixed dose of 600 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0214] For Cycle 3, TTI-622 will be administered at a fixed dose of 600 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0215] For cycles 4-12, TTI-622 will be administered at a fixed dose of 600 mg by IV infusion on days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on days 1 and 15. Lenalidomide will be administered orally on days 1-21 at 25 mg.

[0216] For Cycle 13 and beyond, TTI-622 will be administered at a fixed dose of 600 mg by IV infusion on Days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1 and 15.

[0217] Regimen: 1200mg TTI-622:

[0218] Treatment will be given in 28-day cycles. Lenalidomide will be administered until cycle 12, while TTI-622 and tafamidis will be administered until disease progression or unacceptable toxicity.

[0219] For Cycle 1, TTI-622 will be administered at a fixed dose of 1200 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 4, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0220] For Cycle 2, TTI-622 will be administered at a fixed dose of 1200 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0221] For Cycle 3, TTI-622 will be administered at a fixed dose of 1200 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0222] For cycles 4-12, TTI-622 will be administered at a fixed dose of 1200 mg by IV infusion on days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on days 1 and 15. Lenalidomide will be administered orally on days 1-21 at 25 mg.

[0223] For Cycle 13 and thereafter, TTI-622 will be administered at a fixed dose of 1200 mg by IV infusion on Days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1 and 15.

[0224] Regimen: 1800mg TTI-622:

[0225] Treatment will be given in 28-day cycles. Lenalidomide will be administered until cycle 12, while TTI-622 and tafamidis will be administered until disease progression or unacceptable toxicity.

[0226] For Cycle 1, TTI-622 will be administered at a fixed dose of 1800 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 4, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0227] For Cycle 2, TTI-622 will be administered at a fixed dose of 1800 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0228] For Cycle 3, TTI-622 will be administered at a fixed dose of 1800 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0229] For cycles 4-12, TTI-622 will be administered at a fixed dose of 1800 mg by IV infusion on days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on days 1 and 15. Lenalidomide will be administered orally on days 1-21 at 25 mg.

[0230] For Cycle 13 and beyond, TTI-622 will be administered at a fixed dose of 1800 mg by IV infusion on Days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1 and 15.

[0231] Regimen: 2400mg TTI-622:

[0232] Treatment will be given in 28-day cycles. Lenalidomide will be administered until cycle 12, while TTI-622 and tafamidis will be administered until disease progression or unacceptable toxicity.

[0233] For Cycle 1, TTI-622 will be administered at a fixed dose of 2400 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 4, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0234] For Cycle 2, TTI-622 will be administered at a fixed dose of 2400 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0235] For Cycle 3, TTI-622 will be administered at a fixed dose of 2400 mg by IV infusion on Days 1, 8, 15, and 22. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1, 8, 15, and 22. Lenalidomide will be administered orally at 25 mg on Days 1-21.

[0236] For cycles 4-12, TTI-622 will be administered at a fixed dose of 2400 mg by IV infusion on days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on days 1 and 15. Lenalidomide will be administered orally on days 1-21 at 25 mg.

[0237] For Cycle 13 and beyond, TTI-622 will be administered at a fixed dose of 2400 mg by IV infusion on Days 1 and 15. Tafacitumomab will be administered at 12 mg / kg by IV infusion on Days 1 and 15.

[0238] Optionally, other doses of TTI-622 may be used in the regimen described immediately above, such as 300 mg, 750 mg, 900 mg, 1350 mg, 1500 mg, 2100 mg, or other fixed doses of TTI-622 provided elsewhere herein.

Claims

1. A method of treating cancer in a patient, comprising administering to the patient a combination of a SIRPαFc fusion protein and an anti-CD19 antibody.

2. The method of claim 1, wherein the method further comprises administering an E3 ubiquitin ligase modulator.

3. The method of any one of claims 1-2, wherein one, two or all three of the following occur: i) the SIRPαFc fusion protein is administered Q1W or Q2W; ii) the anti-CD19 antibody is administered Q1W or Q2W; iii) the E3 ubiquitin ligase modulator is administered every day.

4. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy of a SIRPαFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator for at least a first cycle, a second cycle, a third cycle, and a fourth cycle, Each cycle is 28 days. wherein in the first cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 4, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21, wherein in the second cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21, wherein in the third cycle, the SIRPaFc fusion protein is administered on days 1, 8, 15, and 22, the anti-CD19 antibody is administered on days 1, 8, 15, and 22, and the E3 ubiquitin ligase modulator is administered on days 1-21, and Wherein in the fourth cycle, the SIRPaFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase regulator is administered on days 1-21.

5. The method of claim 4, wherein the method continues for at least a fifth cycle and up to a twelfth cycle, and in the fifth cycle to the twelfth cycle, the SIRPαFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase modulator is administered on days 1-21.

6. The method of claim 5, wherein the method continues for at least a thirteenth cycle, wherein in the thirteenth cycle, the SIRPαFc fusion protein is administered on days 1 and 15, the anti-CD19 antibody is administered on days 1 and 15, and the E3 ubiquitin ligase modulator is not administered.

7. The method of any one of claims 1-6, wherein the SIRPαFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg, or 18 mg / kg, or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg, or 2400 mg.

8. The method of any one of claims 1-7, wherein the anti-CD19 antibody is administered at a dose of 12 mg / kg.

9. The method of any one of claims 1-8, wherein the E3 ubiquitin ligase modulator is administered at a dose of 25 mg.

10. A method of treating cancer in a patient, the method comprising administering to the patient a combination therapy of a SIRPαFc fusion protein, an anti-CD19 antibody, and an E3 ubiquitin ligase modulator for at least a first cycle, a second cycle, a third cycle, and a fourth cycle, Each cycle is 28 days. wherein in the first cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 4, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, wherein in the second cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, wherein in the third cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1, 8, 15 and 22, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1, 8, 15 and 22, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21, and Wherein in the fourth cycle, the SIRPaFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1 and 15, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21.

11. The method of claim 10, wherein the method continues for at least the fifth cycle and up to the twelfth cycle, and in the fifth cycle to the twelfth cycle, the SIRPαFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1 and 15, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15, and the E3 ubiquitin ligase modulator is administered at a dose of 25 mg on days 1-21.

12. The method of claim 11, wherein the method continues for at least a thirteenth cycle, wherein in the thirteenth cycle, the SIRPαFc fusion protein is administered at a dose of 4 mg / kg, 10 mg / kg or 18 mg / kg or a fixed dose of 300 mg, 600 mg, 750 mg, 1200 mg, 1350 mg, 1500 mg, 1800 mg, 2100 mg or 2400 mg on days 1 and 15, the anti-CD19 antibody is administered at a dose of 12 mg / kg on days 1 and 15, and the E3 ubiquitin ligase modulator is not administered.

13. The method of any one of claims 1-12, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO:

1.

14. The method of any one of claims 1-13, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO:

2.

15. The method of any one of claims 1-14, wherein the SIRPαFc fusion protein comprises the amino acid sequence of SEQ ID NO:

8.

16. The method of any one of claims 1-13, wherein the SIRPαFc fusion protein comprises a SIRPα polypeptide comprising the amino acid sequence of SEQ ID NO: 1, or a variant thereof having one, two, three, four or five amino acid substitutions compared to the sequence of SEQ ID NO:

1.

17. The method of any one of claims 1 to 16, wherein the anti-CD19 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a HCDR1 region comprising the sequence SY VMH (SEQ ID NO: 11), a HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 12), and a HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 13), and the light chain variable region comprising a LCDR1 region comprising the sequence RSSKSLQNVN GNTYLY (SEQ ID NO: 14), a LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 15), and a LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 16).

18. The method of any one of claims 1-17, wherein the anti-CD 19 antibody comprises a heavy chain variable region of EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQ APGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSS LRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 17) and a light chain variable region of DIVMTQSPATLSLSPGERATLSCRSSKSLQ NVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 18).

19. The method of any one of claims 1-18, wherein the anti-CD 19 antibody comprises an Fc domain comprising an amino acid substitution at position S239 and / or I332, wherein numbering is according to the EU index as in Kabat.

20. The method of claim 19, wherein the anti-CD 19 antibody comprises an Fc domain comprising an S239D amino acid substitution and an I332E amino acid substitution, wherein numbering is according to the EU index as in Kabat.

21. The method of any one of claims 1-20, wherein the anti-CD 19 antibody comprises EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKAL PAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ The heavy chain region of ID NO:19) and DIVMTQSPATLSLSPGERA TLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:20) light chain region.

22. The method of any one of claims 1-21, wherein the E3 ubiquitin ligase modulator comprises lenalidomide, pomalidomide, or thalidomide.

23. The method of any one of claims 1-22, wherein one or both of the following occur: i) the cancer is a CD19-positive cancer and ii) the cancer is a CD47-positive cancer.

24. The method of any one of claims 1-23, wherein the cancer is a hematological malignancy or a solid tumor cancer.

25. A SIRPαFc fusion protein or anti-CD19 antibody for use in treating a patient according to any one of claims 1-24.

26. Use of a SIRPαFc fusion protein or an anti-CD19 antibody in the preparation of a medicament for treating a patient according to any one of claims 1 to 24.

27. A kit comprising a SIRPαFc fusion protein or an anti-CD19 antibody and instructions for use of the method of any one of claims 1-24, and optionally further comprising one or more additional therapeutic agents of the method of any one of claims 1-24.

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